TERT Gene (Telomerase Reverse Transcriptase): Function, Mutations, and Disease Associations
Comprehensive biomedical overview of the TERT gene, including genomic context, protein function, expression, disease links, and mutation spectrum.
Gene Information Card
| Symbol | TERT |
|---|---|
| Full Name | Telomerase reverse transcriptase |
| Gene Type | Protein coding |
| Chromosomal Location | 5p15.33 |
| NCBI Gene ID | 7015 ncbi.nlm.nih.gov/gene/7015 |
| Ensembl ID | ENSG00000164362 |
| UniProt ID | O14746 |
| OMIM ID | 187270 |
| HGNC ID | 11730 |
| Aliases | EST2, TCS1, TRT, hEST2, hTRT, telomerase catalytic subunit |
Description
The TERT gene encodes the catalytic subunit of telomerase, a ribonucleoprotein enzyme that maintains chromosome ends by adding telomeric repeats (TTAGGG) to the 3' end of DNA. TERT is essential for cellular immortality and proliferation, but its expression is tightly regulated in normal somatic cells, where it is typically silenced. Reactivation of TERT is a hallmark of most cancers, enabling unlimited replication. Mutations in TERT are associated with telomere biology disorders, including dyskeratosis congenita, idiopathic pulmonary fibrosis, and aplastic anemia. TERT promoter mutations are among the most frequent non-coding mutations in cancer, creating de novo ETS transcription factor binding sites that drive overexpression.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Dyskeratosis congenita (DC) | Loss-of-function mutations in TERT reduce telomerase activity, leading to progressive telomere shortening and stem cell failure in tissues with high turnover (bone marrow, skin, lungs). | OMIM #127550; multiple case reports and functional studies |
| Idiopathic pulmonary fibrosis (IPF) | Heterozygous TERT mutations cause haploinsufficiency, resulting in short telomeres and alveolar epithelial cell senescence, predisposing to pulmonary fibrosis. | OMIM #614743; GWAS and familial studies |
| Aplastic anemia | TERT mutations impair telomere maintenance in hematopoietic stem cells, leading to bone marrow failure. | ClinVar; case-control studies |
| Various cancers (e.g., melanoma, glioblastoma, bladder cancer) | Somatic TERT promoter mutations (C228T, C250T) create ETS transcription factor binding sites, increasing TERT expression and enabling telomere maintenance, contributing to tumor immortalization. | COSMIC; multiple cancer genomics studies |
| Hepatocellular carcinoma | TERT promoter mutations are the most frequent genetic alteration, driving telomerase reactivation and tumor progression. | COSMIC; TCGA data |
| Revesz syndrome | Severe variant of dyskeratosis congenita with biallelic TERT mutations, presenting with exudative retinopathy and bone marrow failure. | OMIM #268130; case reports |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | High (nTPM ~ 50-100) | High expression in germ cells |
| Bone marrow | Low (nTPM ~ 5-10) | Hematopoietic stem cells express TERT |
| Thymus | Low (nTPM ~ 5) | Immune cell progenitors |
| Skin | Very low (nTPM < 1) | Basal keratinocytes have low expression |
| Lung | Very low (nTPM < 1) | Alveolar cells mostly silent |
| Liver | Very low (nTPM < 1) | Hepatocytes silent; expression in stem cells |
| Brain | Very low (nTPM < 1) | Neurons silent; neural stem cells may express |
| Heart | Very low (nTPM < 1) | Cardiomyocytes silent |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical cancer) | High (nTPM ~ 100) | Constitutive expression due to HPV E6 and promoter mutations |
| A549 (lung carcinoma) | Moderate (nTPM ~ 50) | TERT promoter mutation (C228T) |
| U87MG (glioblastoma) | High (nTPM ~ 80) | TERT promoter mutation (C250T) |
| MCF7 (breast cancer) | Low (nTPM ~ 10) | Expression variable; often low in ER+ lines |
| HepG2 (hepatocellular carcinoma) | High (nTPM ~ 70) | TERT promoter mutation (C228T) |
| K562 (chronic myeloid leukemia) | Moderate (nTPM ~ 30) | Expression via alternative mechanisms |
| Normal fibroblasts (e.g., WI-38) | Very low (nTPM < 1) | Silent; senescence upon serial passage |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| C228T (promoter) | SNV (non-coding) | ~50-80% in melanoma, bladder, glioblastoma; ~10-20% in many cancers | Creates ETS binding site (GABP), increases TERT transcription |
| C250T (promoter) | SNV (non-coding) | ~10-20% in melanoma, glioblastoma | Similar effect as C228T, creates ETS site |
| A202T (exonic) | Missense | Rare in familial pulmonary fibrosis | Reduces telomerase activity, haploinsufficiency |
| V747M (exonic) | Missense | Rare in dyskeratosis congenita | Impairs catalytic activity, telomere shortening |
| K570N (exonic) | Missense | Rare in aplastic anemia | Reduced processivity |
| R865H (exonic) | Missense | Rare in dyskeratosis congenita | Disrupts reverse transcriptase domain |
| F1127L (exonic) | Missense | Rare in pulmonary fibrosis | Decreased telomerase activity |
| Large deletions | Structural | Very rare | Loss of function, severe telomere shortening |
Mutation functional classification
Loss of Function (LOF)
Most TERT coding mutations are loss-of-function, leading to reduced telomerase activity and progressive telomere shortening. These are typically inherited in an autosomal dominant or recessive manner and cause telomere biology disorders such as dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia. Haploinsufficiency is a common mechanism.
Gain of Function (GOF)
TERT promoter mutations are gain-of-function, increasing TERT expression by creating de novo binding sites for ETS transcription factors (e.g., GABP). This promotes telomere maintenance and cellular immortalization, contributing to oncogenesis. No gain-of-function coding mutations are commonly reported.
Dominant Negative (DN)
Some TERT missense mutations may exert a dominant-negative effect by interfering with the assembly or function of the telomerase complex, even in the presence of a wild-type allele. However, most pathogenic variants act via haploinsufficiency rather than dominant-negative mechanisms.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Telomere maintenance via telomerase (Reactome: R-HSA-157579)
• Senescence-associated secretory phenotype (SASP)
• p53 signaling pathway (KEGG: hsa04115)
• Cell cycle regulation (KEGG: hsa04110)
• Wnt signaling (crosstalk with TERT)
• NF-kB signaling (TERT modulates)
• DNA damage response (TERT protects telomeres)
Protein Summary
The TERT protein is a 1132-amino acid reverse transcriptase that catalyzes the addition of telomeric repeats to chromosome ends. It contains an N-terminal RNA-binding domain (TRBD), a central reverse transcriptase domain, and a C-terminal extension. TERT functions as the catalytic core of telomerase, complexing with the RNA component (TERC) and accessory proteins (e.g., dyskerin, NOP10, NHP2, GAR1). TERT is localized to the nucleus, specifically to Cajal bodies and telomeres during S phase. Its expression is tightly regulated at transcriptional, post-transcriptional, and post-translational levels. In addition to telomere elongation, TERT has non-canonical functions, including modulation of Wnt signaling, NF-kB activity, and mitochondrial function, contributing to cell survival and stress resistance.
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| TERT Knockout HEK293 Cell Line | EDJ-KQ2603 | Human | 7015 | Details Get a Quote |
| TERT Knockout A-549 Cell Line | EDJ-KQ23309 | Human | 7015 | Details Get a Quote |
| TERT Knockout HCT 116 Cell Line | EDJ-KQ23310 | Human | 7015 | Details Get a Quote |
| TERT Knockout HeLa Cell Line | EDJ-KQ23311 | Human | 7015 | Details Get a Quote |
| TERT (c.3184G>A )Point Mutation in HAP1 Cell Line | EDC03613 | Human | 7015 | Details Get a Quote |
| TERT (c.2970+74C>T )Point Mutation in HAP1 Cell Line | EDC03614 | Human | 7015 | Details Get a Quote |
| TERT (c.336del )Point Mutation in HAP1 Cell Line | EDC03615 | Human | 7015 | Details Get a Quote |
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